Inference of Tumor Evolution during Chemotherapy by Computational Modeling and In Situ Analysis of Genetic and Phenotypic Cellular Diversity

被引：212

作者：

Almendro, Vanessa ^{[1
,2
,3
,4
]}

Cheng, Yu-Kang ^{[5
,6
]}

Randles, Amanda ^{[5
,6
,7
]}

Itzkovitz, Shalev ^{[8
,9
,10
,11
]}

Marusyk, Andriy ^{[1
,2
,3
]}

Ametller, Elisabet ^{[4
]}

Gonzalez-Farre, Xavier ^{[4
]}

Munoz, Montse ^{[4
]}

Russnes, Hege G. ^{[12
,13
,14
]}

Helland, Aslaug ^{[12
,15
,16
]}

Rye, Inga H. ^{[12
,13
]}

Borresen-Dale, Anne-Lise ^{[12
,13
]}

Maruyama, Reo ^{[1
,2
,3
]}

van Oudenaarden, Alexander ^{[8
,9
,10
,17
,18
]}

Dowsett, Mitchell ^{[19
]}

Jones, Robin L. ^{[19
,20
]}

Reis-Filho, Jorge ^{[19
,21
]}

Gascon, Pere ^{[4
]}

Goenen, Mithat ^{[22
]}

Michor, Franziska ^{[5
,6
]}

Polyak, Kornelia ^{[1
,2
,3
,23
,24
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[4] Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer, Dept Med Oncol, E-08036 Barcelona, Spain

[5] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[6] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[7] Lawrence Livermore Natl Lab, Ctr Appl Sci Comp, Livermore, CA 94550 USA

[8] MIT, Dept Phys, Cambridge, MA 02139 USA

[9] MIT, Dept Biol, Cambridge, MA 02139 USA

[10] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[11] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[12] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, N-0424 Oslo, Norway

[13] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0316 Oslo, Norway

[14] Oslo Univ Hosp, Dept Pathol, N-0424 Oslo, Norway

[15] Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway

[16] Univ Oslo, Fac Med, Inst Clin Med, N-0316 Oslo, Norway

[17] Royal Netherlands Acad Arts & Sci, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands

[18] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands

[19] Royal Marsden Hosp, Breakthrough Breast Canc Res Ctr, Inst Canc Res, London SW3 6JJ, England

[20] Seattle Canc Care Alliance, Seattle, WA 98109 USA

[21] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[22] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[23] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[24] Broad Inst, Cambridge, MA 02142 USA

来源：

CELL REPORTS | 2014年 / 6卷 / 03期

关键词：

PATHOLOGICAL COMPLETE RESPONSE; BREAST-CANCER; NEOADJUVANT CHEMOTHERAPY; PREOPERATIVE CHEMOTHERAPY; HETEROGENEITY; RESISTANCE; PROGRESSION; CARCINOMAS; CISPLATIN; REVEALS;

D O I：

10.1016/j.celrep.2013.12.041

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

引用

页码：514 / 527

页数：14

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